ABSTRACT
A new class of potent PI3Kα inhibitors is identified based on aryl substituted morpholino-triazine scaffold. The identified compounds showed not only a high level of enzymatic and cellular potency in nanomolar range but also high oral bioavailability. The three lead molecules (based on their in vitro potency) when evaluated further for in vitro metabolic stability as well as pharmacokinetic profile led to the identification of 26, as a candidate for further development. The IC50 and EC50 value of 26 is 60 and 500 nM, respectively, for PI3Kα enzyme inhibitory activity and ovarian cancer (A2780) cell line. The identified lead also showed a high level of microsomal stability and minimal inhibition activity for CYP3A4, CYP2C19, and CYP2D6 at 10 µM concentrations. The lead compound 26, demonstrated excellent oral bioavailability with an AUC of 5.2 µM at a dose of 3 mpk in mice and found to be well tolerated in mice when dosed at 30 mpk BID for 5 days.
ABSTRACT
Over activation of the PI3K/Akt/mTOR pathway is found in most cancer tumor types. Controlled regulation of this pathway using PI3K inhibitors can provide therapeutic significance in cancer treatment. Herein, we report the synthesis and evaluation of pyrrolotriazine based novel small molecules as pan-PI3K inhibitors. The SAR studies based on in vitro potency along with microsomal metabolic stability screening, identified 18 as a preclinical lead found to be suitable for in vivo evaluation. The identified lead was also found to be a selective inhibitor of PI3K isoforms and mTOR when screened across a panel of 23 homologous kinases.
Subject(s)
Phosphoinositide-3 Kinase Inhibitors , Protein Kinase Inhibitors/chemical synthesis , Triazines/chemistry , Binding Sites , Catalytic Domain , Cell Line, Tumor , Cell Proliferation/drug effects , Drug Evaluation, Preclinical , Enzyme Activation/drug effects , Humans , Microsomes/metabolism , Molecular Docking Simulation , Phosphatidylinositol 3-Kinases/metabolism , Protein Binding , Protein Kinase Inhibitors/metabolism , Protein Kinase Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Signal Transduction , TOR Serine-Threonine Kinases/metabolism , Triazines/metabolism , Triazines/pharmacologyABSTRACT
Two new classes of diphenylether inhibitors of p38alpha MAP kinase are described. Both chemical classes are based on a common diphenylether core that is identified by simulated fragment annealing as one of the most favored chemotypes within a prominent hydrophobic pocket of the p38alpha ATP-binding site. In the fully elaborated molecules, the diphenylether moiety acts as an anchor occupying the deep pocket, while polar extensions make specific interactions with either the adenine binding site or the phosphate binding site of ATP. The synthesis, crystallographic analysis, and biological activity of these p38alpha inhibitors are discussed.
